Persistent pain is stressful and produces mood disturbances such as anxiety and impaired reward motivation. While exercise is widely agreed to be analgesic, rodent studies have generally employed highly stressful forced exercise paradigms that may not only produce stress-induced analgesia, but may also exacerbate co-morbid mood disturbances such as anxiety. In order to dissociate exercise-induced analgesia from stress-induced analgesia, we are comparing a non-stressful exercise paradigm (voluntary running on a running wheel) with a highly stressful exercise paradigm (forced running on a treadmill) in terms of pain, anxiety and impaired reward. We are also studying changes to brain areas that mediate these systems. To date, we have established that despite persistent hind limb pain, rodents voluntarily engaged in wheel running, up to 2 km per day. In these animals, voluntary exercise was analgesic, as measured by weight bearing capacity on the injured paw as well as by thermal withdrawal latency. Furthermore, voluntary exercise had stress-reducing properties, as evidenced by increased heart rate variability and lower levels of plasma corticosterone. We have analyzed data obtained during this to study and a research manuscript has been submitted for review. This study will allow us to better understand how exercise, specifically voluntary exercise, produces beneficial effects in persistent pain states.